Zinc-fingers, which widely exist in eukaryotic cell and play crucial roles in life processes, depend on the binding of zinc ion for their proper folding. To computationally study the zinc coupled folding of the zinc-fingers, charge transfer and metal induced protonation/deprotonation effects have to be considered. Here, by attempting to implicitly account for such effects in classical molecular dynamics and performing intensive simulations with explicit solvent for the peptides with and without zinc binding, we investigate the folding of the Cys 2 His 2 type zinc-finger motif and the coupling between the peptide folding and zinc binding. We find that zinc ion not only stabilizes the native structure, but also participates in the whole folding process. It binds to the peptide at early stage of folding, and directs or modulates the folding and stabilizations of the component β-hairpin and α-helix. Such a crucial role of zinc binding is mediated by the packing of the conserved hydrophobic residues. We also find that the packing of the hydrophobic residues and the coordination of the native ligands are coupled. Meanwhile, the processes of zinc binding, mis-ligation, ligand exchange and zinc induced secondary structure conversion, as well as the water behaviour, due to the involvement of zinc ion are characterized. Our results are in good agreement with related experimental observations, and provide significant insight into the general mechanisms of the metal-cofactor dependent protein folding and other metal induced conformational changes of biological importance.

3,4-Dihydroxyphenylalanine (DOPA) is the noncanonical amino acid widely found in mussel holdfast proteins, which is proposed to be responsible for their strong wet adhesion. This feature has also inspired the successful development of a range of DOPA-containing synthetic polymers for wet adhesions and surface coating. Despite the increasing applications of DOPA in material science, the underlying mechanism of DOPA-wet surface interactions remains unclear. In this work, we studied DOPA-surface interactions one bond at a time using atomic force microscope (AFM) based single molecule force spectroscopy. With our recently developed "multiple fishhook" protocol, we were able to perform high-throughput quantification of the binding strength of DOPA to various types of surfaces for the first time. We found that the dissociation forces between DOPA and nine different types of organic and inorganic surfaces are all in the range of 60-90 pN at a pulling speed of 1000 nm s(-1), suggesting the strong and versatile binding capability of DOPA to different types of surfaces. Moreover, by constructing the free energy landscape for the rupture events, we revealed several distinct binding modes between DOPA and different surfaces, which are directly related to the chemistry nature of the surfaces. These results explain the molecular origin of the versatile binding ability of DOPA. Moreover, we could quantitatively predict the relationship between DOPA contents and the binding strength based on the measured rupture kinetics. These serve as the bases for the quantitative prediction of the relationship between DOPA contents and adhesion strength to different wet surfaces, which is important for the design of novel DOPA based materials.

The folding process of trpzip2 beta-hairpin is studied by the replica exchange molecular dynamics (REMD) and normal MD simulations, aiming to understand the folding mechanism of this unique small, stable, and fast folder, as well as to reveal the general principles in the folding of beta-hairpins. According to our simulations, the TS ensemble is mainly characterized by a largely formed turn and the interaction between the inner pair of hydrophobic core residues. The folding is a zipping up of hydrogen bonds. However, the nascent turn has to be stabilized by the partially formed hydrophobic core to cross the TS. Thus our folding picture is in essence a blend of hydrogen bond-centric and hydrophobic core-centric mechanism. Our simulations provide a direct evidence for a very recent experiment (Du et al., Proc Natl Acad Sci USA 2004;101:15915-15920), which suggests that the turn formation is the rate-limiting step for beta-hairpin folding and the unfolding is mainly determined by the hydrophobic interactions. Besides, the relationship between hydrogen bond stabilities and their relative importance in folding are investigated. It is found that the hydrogen bonds with higher stabilities need not play more important roles in the folding process, and vice versa.

The downhill folding observed experimentally for a small protein BBL is studied using off-lattice Gō-like model. Our simulations show that the downhill folding has low cooperativity and is barrierless, which is consistent with the experimental findings. As an example of comparison in detail, the two-state folding behavior of proteins, for example, protein CI2, is also simulated. By observing the formation of contacts between the residues for these two proteins, it is found that the physical origin of the downhill folding is due to the deficiency of nonlocal contacts which determine the folding cooperatively. From a statistics on contacts of the native structures of 17 well-studied proteins and the calculation of their cooperativity factors kappa2 based on folding simulations, a strong correlation between the number of nonlocal contacts per residue NN and the factors kappa2 is obtained. Protein BBL with a value of NN = 0.73 has the lowest cooperativity factor kappa2 = 0.34 among all 17 proteins. A crossover around NNc approximately 0.9 could be defined to separate the two-state folders and the downhill folder roughly. A protein would behave downhill folding when its NN = NNc. For proteins with their NN values are about (or slightly larger than) NNc, the folding behaves with low cooperativity and the barriers are small, showing a weak two-state behavior or a downhill-like behavior. Furthermore, simulations on mutants of a two-state folder show that a mutant becomes a downhill folder when its NN is reduced to a value smaller than NNc. These could enable us to identify the downhill folding or the cooperative two-state folding behavior solely from the native structures of proteins.

Interferon-inducible transmembrane protein IFITM3 was known to restrict the entry of a wide spectrum of viruses to the cytosol of the host. The mechanism used by the protein to restrict viral entry is unclear given the unavailability of the membrane topology and structures of the IFITM family proteins. Systematic site-directed spin labeling (SDSL) and electron paramagnetic resonance (EPR) studies of IFITM3 in detergent micelles identified a single, long transmembrane helix in the C-terminus and an intramembrane segment in the N-terminal hydrophobic region. Solution NMR studies of the same sample verified the secondary structure distribution and demonstrated two rigid regions interacting with the micellar surface. The resulting membrane topology of IFITM3 supports the mechanism of an enhanced restricted membrane hemi-fusion.

Metal coordination bonds are widely found in natural adhesives and load-bearing and protective materials, in which they are thought to be responsible for the high mechanical strength and toughness. However, it remains unknown how metal−ligand complexes could give rise to such superb mechanical properties. Here, we developed a singlechain nanoparticle based force spectroscopy to directly quantify the mechanical properties of individual catechol− Fe 3+ complexes, the key elements accounting for the high toughness and extensibility of byssal threads of marine mussels. We found that catechol−Fe 3+ complexes possess a unique combination of mechanical features, including high mechanical stability, fast reformation kinetics, and stoichiometry-dependent mechanics. Therefore, they can serve as sacrificial bonds to efficiently dissipate energy in the materials, quickly recover the mechanical properties when load is released, and respond to pH and Fe 3+ concentrations. Especially, we revealed that the bis-catechol−Fe 3+ complex is mechanically ∼90% stronger than the tris-catechol−Fe 3+ complex. Quantum calculation study suggested that the distinction between mechanical strength and thermodynamic stability of catechol−Fe 3+ complexes is due to their different mechanical rupture pathways. Our study provides the nanoscale mechanistic understanding of the coordination bond-mediated mechanical properties of biogenetic materials, and could guide future rational design and regulation of the mechanical properties of synthetic materials.

We study a large data set of protein structure ensembles of very diverse sizes determined by nuclear magnetic resonance. By examining the distance-dependent correlations in the displacement of residues pairs and conducting finite size scaling analysis it was found that the correlations and susceptibility behave as in systems near a critical point implying that, at the native state, the motion of each amino acid residue is felt by every other residue up to the size of the protein molecule. Furthermore certain protein's shapes corresponding to maximum susceptibility were found to be more probable than others. Overall the results suggest that the protein's native state is critical, implying that despite being posed near the minimum of the energy landscape, they still preserve their dynamic flexibility.Protein molecules are formed by large unbranched chains of amino acids, which turn into a complex folded shape as free energy is minimized. It is this highly specific three-dimensional folded structure, known as native state, that makes the protein capable of performing its biological function [1]. Proteins carry out their functions by switching from one shape to another, even transiently, as for instance when it recognizes and binds with another molecule. To achieve such performance the structure of the native state must be very susceptible to sense the signal and switch to another shape, but also be stable enough to warrant reproducibility. It is well known that these apparently contradictory demands are exhibited by systems near a critical point because of the coexistence of maximum susceptibility and long range correlations [2-6].These views are discussed on a number of recent reports emphasizing different aspects of critical fluctuations in the protein equilibrium dynamics. This includes the geometric properties [7], the slowness in relaxation in the dynamics of large biomolecules [8], the role of their low-frequency global modes [9,10] in the proteins' functional dynamics, the overlap of the large-scale conformational change in allosteric transitions and the low frequency normal modes [11], the role of the water surrounding the molecule [12], as well as the near-critical states emerging in the sequential correlations of protein families [3].Although it is often recognized that the available data seems still far from being the ideal to test for criticality, we propose here an approach to investigate this issue. We use a large number of protein structure ensembles determined by solution nuclear magnetic resonance (NMR). Since each ensemble contains different structures of the same protein, the basic idea is to assume that each of structures can be seen as a hypothetical instantiation of the spontaneous conformational changes that the protein exhibit through time. By examining the distance-dependent correlations in the displacement of residue pairs and conducting finite size scaling analysis it is shown that the correlations and susceptibility behave as expected in systems near a critical point. The results imply t...

The ability of signal detection and transduction of the Hodgkin-Huxley neuronal systems, associated with rhythmic oscillations in the presence of external modulations, is studied. Both inhibitory and excitatory modulations, regarded as the total effects of the environment in which the neurons are located, are able to modulate the frequencies of the rhythmic oscillations of the neurons. Either subthreshold or suprathreshold rhythmic oscillations can provide the neural system with an effect of frequency selection in processing external signal. Resonance among the noise, the noise-induced oscillation, and the signal enhances intensively the capability of the neurons in processing the weak signal, especially when frequency of the signal is around that of the noise-induced rhythmic oscillation. Thus, the neuronal system can be adjusted to an optimal sensitive state for signal processing through the environmental modulations.